CN112979523A

CN112979523A - Preparation method of chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound

Info

Publication number: CN112979523A
Application number: CN202110493558.8A
Authority: CN
Inventors: 汪志勇; 戚鸣; 李金东
Original assignee: University of Science and Technology of China USTC
Current assignee: University of Science and Technology of China USTC
Priority date: 2021-01-26
Filing date: 2021-05-07
Publication date: 2021-06-18
Anticipated expiration: 2041-05-07
Also published as: CN112979523B

Abstract

The invention provides a preparation method of a chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound, which comprises the following steps: in the presence of a chiral metal compound, mixing and reacting enol silicon ether and phenylglyoxal monohydrate or substituted phenylglyoxal monohydrate in a solvent to obtain a chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound, wherein the reaction equation is shown in formula 1;

r of said silyl enol ether₁Is phenyl or furan structure, and substituent R in substituted phenylglyoxal monohydrate₂One or more selected from hydrogen atom, halogen, methyl, methoxy, nitro and trifluoromethyl, and the substituent is at ortho-position, meta-position or para-position of the benzene ring. The chiral metal compound can efficiently catalyze the asymmetric Mukaiyama aldol reaction of the phenylglyoxal monohydrate compound with high enantioselectivity, provides a new method for synthesizing the 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound, solves the problem of harsh conditions in the original reaction, and is more environment-friendly.

Description

Preparation method of chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound

Technical Field

The invention belongs to the technical field of organic synthesis, and relates to a preparation method of a chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound.

Background

The asymmetric catalytic reaction is a key means for preparing chiral substances, and the asymmetric Mukaiyama aldol reaction is an important method for constructing a C-C bond and is related to bond application in the synthesis preparation of biological medicines and natural products.

Since the discovery of Aldol reaction, the Aldol reaction has important application in the construction of various important carbon skeletons, and the research on the Aldol reaction is still in depth. In 2016, Ikemoto et al selected glyoxylate as an electrophile to participate in asymmetric aldol reactions, and the product structure was the key backbone of anti-AIDS drugs (org. Process Res. Dev.,2016,20, 1615.). In 2020, Da subject group can efficiently produce 2-hydroxydicarbonyl compounds with high enantioselectivity by catalyzing aldol reaction between glyoxylic acid ester and aldehyde compounds by enzyme (org. lett.2020,22,4444.). In 1973, Mukaiyama group prepared β -hydroxyketone compounds using aldol reaction of enolsilyl ethers with carbonyl compounds, further deepened the study of the aldol reaction and opened up a new field of Mukaiyama aldol reaction. However, the use of the Mukaiyama aldol reaction involving dicarbonyl compounds is greatly limited due to side reactions. In 2010, the Feng project group catalyzed Mukaiyama aldol reaction by using chiral nickel complex to prepare the 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound (Synlett, 2011,7, 903). The compound has important application in biomedicine and natural product skeleton construction after being derived. The compound was first prepared from this group of subjects using an amide or alkene carbamate to react with phenylketoaldehyde (chem. The reaction provides a method for preparing the compound with a nitrene type reaction, and the reaction has high enantioselectivity, convenience and high efficiency. However, the preparation of 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compounds by Mukaiyama aldol reaction has the problems of unobvious enantioselectivity and harsh reaction conditions, the reaction needs to be protected by strict inert gas, and particularly, a strong acid such as hydrochloric acid is needed in the process of converting the reaction intermediate into a final product, so that the reaction has great limitations in aspects of environmental protection, application and the like. The method for preparing the 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound has the characteristic of high enantioselectivity, and the ee value of the product is more prominent; and the reaction can be converted into a final product in one step without intermediate conversion, the reaction condition is mild, and the method is green and environment-friendly.

Despite the breakthrough progress of the aldol reaction, the asymmetric Mukaiyama aldol reaction of dicarbonyl compounds still needs to be researched and developed, and the applicability of the substrate and the enantioselectivity of the reaction also need to be further improved.

Disclosure of Invention

The invention aims to provide a preparation method of a chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound. The invention also provides a proline derived chiral ligand and a preparation method thereof; and a chiral metal complex formed by complexing the ligand with a metal; and a method for preparing a series of 1, 4-diphenyl-2-hydroxy-1, 4-dibutyrone compounds with high enantioselectivity by using the chiral metal compound as a catalyst to catalyze asymmetric Mukaiyama aldol reaction of phenylketoaldehyde monohydrate or substituted phenylketoaldehyde monohydrate.

To this end, the present invention provides a method for preparing a chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound, comprising: in the presence of a chiral metal compound, mixing and reacting enol silicon ether and phenylglyoxal monohydrate or substituted phenylglyoxal monohydrate in a solvent to obtain a chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound; wherein the mol ratio of the enol silyl ether to the chiral metal compound is (10-20): 1, the reaction is shown in the following formula 1:

r of said silyl enol ether₁Is phenyl or furan structure, and substituent R in substituted phenylglyoxal monohydrate₂One or more selected from hydrogen atom, halogen, methyl, methoxy, nitro and trifluoromethyl, and the substituent R₂At the ortho, meta or para position of the phenyl ring.

Further, the mol ratio of the enol silyl ether to the chiral metal compound is (10-18): 1.

further, the chiral metal compound has a general structure represented by A or A',

wherein X^-Selected from the group consisting of triflate, halide, acetate and nitrateOne or more of; m is selected from one or more of metallic copper, iron and zinc; r_mDenotes a number m of radicals R, R'_nThe expression n groups R ', R, R' are respectively and independently selected from one or more of hydrogen atoms, alkyl groups of C1-C5, alkoxy groups of C1-C5 and perfluoroalkyl groups of C1-C5, m is an integer of 1-5, n is an integer of 1-5, R, R 'is respectively and independently at ortho position, meta position or para position of a benzene ring, and the substitution positions of R and R' on the benzene ring in the same ligand are the same or different.

Further, the concentration of the phenylglyoxal monohydrate or the substituted phenylglyoxal monohydrate is 0.1-10 mmol/mL; preferably, the concentration of the phenylglyoxal monohydrate or the substituted phenylglyoxal monohydrate is 0.1-5 mmol/mL.

Further, the temperature of the mixing reaction is-20-30 ℃; preferably, the temperature of the mixing reaction is-20-20 ℃; more preferably, the temperature of the mixing reaction is-10-20 ℃.

Further, the time of the mixing reaction is 1-2.5 h.

Further, the concentration of the chiral metal compound participating in the reaction is 0.5-5 mmol/mL.

Further, the solvent is ketone, nitrile or halogen-containing compound; preferably, the solvent is acetone, acetonitrile or chloroform.

Meanwhile, the invention also provides the following technical scheme:

a proline derived chiral ligand, characterized in that said chiral ligand is represented by L or L':

R_mdenotes a number m of radicals R, R'_nRepresents n groups R ', wherein R, R ' are respectively and independently selected from one or more of hydrogen atoms, alkyl groups of C1-C5, alkoxy groups of C1-C5 and perfluoroalkyl groups of C1-C5, m is an integer of 1-5, n is an integer of 1-5, R, R ' are respectively and independently arranged at the ortho-position and the meta-position of a benzene ringAnd the substituted position of R on the benzene ring and the substituted position of R' on the benzene ring in the same ligand are the same or different.

Ligands meeting the above conditions may have the structure shown below:

<2> a method for preparing the chiral ligand of <1> above, comprising the steps of:

performing Grignard reaction on proline methyl ester A with a protecting group and brominated aromatic hydrocarbon to obtain an amino alcohol compound B;

reducing the amino alcohol compound B by using a reducing agent, and removing protection to obtain amino alcohol C;

reacting the amino alcohol C with a salicylaldehyde compound D to obtain a chiral ligand L;

or the proline methyl ester A 'with the protecting group and the brominated aromatic hydrocarbon are subjected to Grignard reaction to obtain an amino alcohol compound B';

reducing the amino alcohol compound B 'by using a reducing agent, and removing protection to obtain amino alcohol C';

reacting amino alcohol C 'with salicylaldehyde compound D to obtain chiral ligand L';

in the formula, the substituent R in the brominated aromatic hydrocarbon is selected from one or more of hydrogen atoms, alkyl of C1-C5, alkoxy of C1-C5 and perfluoroalkyl of C1-C5, m is an integer of 1-5, R is an integer of 1-5_mRepresenting m groups R, wherein the substituent R in the brominated aromatic hydrocarbon is at the ortho-position, meta-position or para-position of a benzene ring; preferably, the reducing agent is hydrogen.

<3> a chiral metal complex having a general structure represented by the following A or A' and formed by a coordination complex reaction of a chiral ligand according to the above <1> with a metal salt,

wherein X^-One or more selected from triflate, halide, acetate and nitrate; m is selected from one or more of metallic copper, iron and zinc; r_mDenotes a number m of radicals R, R'_nThe expression n groups R ', R, R' are respectively and independently selected from one or more of hydrogen atoms, alkyl groups of C1-C5, alkoxy groups of C1-C5 and perfluoroalkyl groups of C1-C5, m is an integer of 1-5, n is an integer of 1-5, R, R 'is respectively and independently at ortho position, meta position or para position of a benzene ring, and the substitution position of R on the benzene ring and the substitution position of R' on the benzene ring in the same ligand are the same or different.

A method for preparing a chiral metal complex, the method comprising: adding a metal salt, a base and the chiral ligand according to the above <1> to a reaction solvent, and mixing to react, wherein the metal ion in the metal salt is at least one selected from the group consisting of copper, iron and zinc; the alkali is selected from one or more of triethylamine, DABCO, sodium carbonate and lithium carbonate. Triethylamine and DABCO are organic bases, and sodium carbonate and lithium carbonate are inorganic bases.

<5> according to the process of <4> above, the molar ratio of the chiral ligand to the metal salt and the base is (0.2-2.0): (0.2-2.0): (0.2-2.0).

<6> according to the process <4> above, the reaction solvent is selected from one or more of ketones, nitriles or halogen-containing compounds; preferably, the reaction solvent is selected from one or more of acetone, acetonitrile, dichloromethane or chloroform.

The chiral metal compound provided by the invention can efficiently catalyze asymmetric Mukaiyama aldol reactions of phenylglyoxal monohydrate and substituted phenylglyoxal monohydrate. The 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound with high enantioselectivity is obtained by the reaction. The metal ligand compound provided by the invention solves the problem of severe conditions in the Mukaiyama aldol reaction of the existing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound, develops a new catalyst for preparing an important organic synthesis intermediate, and has important significance for the development and application of organic reactions.

Drawings

FIG. 1 is a NMR hydrogen spectrum of the product s-3aa obtained in example 7;

FIG. 2 is a NMR carbon spectrum of the product s-3aa obtained in example 7;

FIG. 3 is a NMR hydrogen spectrum of the product s-3ba obtained in example 8;

FIG. 4 is a carbon NMR spectrum of s-3ba, a product obtained in example 8;

FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the product s-3ca obtained in example 9;

FIG. 6 is a nuclear magnetic resonance carbon spectrum of the product s-3ca obtained in example 9;

FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of the product s-3da obtained in example 10;

FIG. 8 is a nuclear magnetic resonance carbon spectrum of the resulting product s-3da in example 10;

FIG. 9 is a nuclear magnetic resonance fluorine spectrum of the product s-3da obtained in example 10;

FIG. 10 is a nuclear magnetic resonance hydrogen spectrum of the product s-3ea obtained in example 11;

FIG. 11 is a nuclear magnetic resonance carbon spectrum of the product s-3ea obtained in example 11;

FIG. 12 is a nuclear magnetic resonance hydrogen spectrum of the product s-3fa obtained in example 12;

FIG. 13 is a NMR carbon spectrum of the product s-3fa obtained in example 12;

FIG. 14 is a NMR spectrum of the product s-3ga obtained in example 13;

FIG. 15 is a NMR carbon spectrum of the product s-3ga obtained in example 13;

FIG. 16 is a nuclear magnetic resonance fluorine spectrum of the product s-3ga obtained in example 13;

FIG. 17 is a nuclear magnetic resonance hydrogen spectrum of the product s-3ha obtained in example 14;

FIG. 18 is a NMR carbon spectrum of the product s-3ha obtained in example 14;

FIG. 19 is a nuclear magnetic resonance hydrogen spectrum of the product s-3ia obtained in example 15;

FIG. 20 is a NMR carbon spectrum of the product s-3ia obtained in example 15;

FIG. 21 is a nuclear magnetic resonance hydrogen spectrum of the product s-3ja obtained in example 16;

FIG. 22 is a NMR carbon spectrum of the product s-3ja obtained in example 16;

FIG. 23 is a nuclear magnetic resonance hydrogen spectrum of the product s-3ka obtained in example 17;

FIG. 24 is a nuclear magnetic resonance carbon spectrum of the product s-3ka obtained in example 17;

FIG. 25 is a nuclear magnetic resonance hydrogen spectrum of the product s-3la obtained in example 18;

FIG. 26 is a NMR carbon spectrum of the product s-3la obtained in example 18;

FIG. 27 is a nuclear magnetic resonance hydrogen spectrum of the product s-3ma obtained in example 19;

FIG. 28 is a NMR carbon spectrum of the product s-3ma obtained in example 19;

FIG. 29 is a nuclear magnetic resonance hydrogen spectrum of the product s-3na obtained in example 20;

FIG. 30 is a nuclear magnetic resonance carbon spectrum of the product s-3na obtained in example 20;

FIG. 31 is a nuclear magnetic resonance fluorine spectrum of the product s-3na obtained in example 20;

FIG. 32 is a NMR hydrogen spectrum of the product s-3oa obtained in example 21;

FIG. 33 is a NMR carbon spectrum of the product s-3oa obtained in example 21;

FIG. 34 is a NMR hydrogen spectrum of a product s-3ab obtained in example 22;

FIG. 35 is a NMR carbon spectrum of the product s-3ab obtained in example 22.

Detailed Description

The present invention will be further described with reference to the accompanying drawings and specific embodiments.

In a first aspect, the present invention provides a chiral metal complex. The chiral metal compound has a general structure represented by the following A or A':

X^-one or more selected from trifluoromethanesulfonate, halogen ions, acetate or nitrate; m is selected from one or more of metal copper, iron or zinc; r_mDenotes a number m of radicals R, R'_nThe ligand is represented by n groups R ', substituents R, R' on a benzene ring are respectively and independently selected from one or more of hydrogen atoms, alkyl of C1-C5, alkoxy of C1-C5 and perfluoroalkyl of C1-C5, m is an integer of 1-5, n is an integer of 1-5, R, R 'is respectively and independently at ortho-position, meta-position or para-position of the benzene ring, and the substitution position of R on the benzene ring and the substitution position of R' on the benzene ring in the same ligand are the same or different.

Wherein the ligand is a proline derived compound and has the following structural general formula L or L':

ligands meeting the above conditions may have the structure shown below:

the invention starts from proline ester, and can prepare ligand L or L' by a simple three-step method:

carrying out Grignard reaction on proline methyl ester A (A ') with a protecting group and brominated aromatic hydrocarbon to obtain an amino alcohol compound B (B');

reducing the amino alcohol compound B (B ') by hydrogen, and deprotecting to obtain amino alcohol C (C');

the reaction of the amino alcohol C (C ') with the salicylaldehyde compound D (D) gives the chiral ligand L (L').

R_mThe substituent R on the benzene ring is one or more selected from hydrogen atoms, alkyl of C1-C5, alkoxy of C1-C5 and perfluoroalkyl of C1-C5, m is an integer of 1-5, and R is in ortho-position, meta-position or para-position of the benzene ring.

In a second aspect, the present invention provides a method for preparing a chiral metal complex represented by the general formula (1): the use of metal salts with ligands can be generated in situ under the action of a base.

The chiral metal compound shown above is prepared by using the ligand, the metal salt and the base in a molar ratio of (0.2-2.0): (0.2-2.0): (0.2-2.0). Preferably (0.2-1.5): (0.2-1.5): (0.2-1.5).

The metal salt according to the present invention may be copper, iron or zinc, which are well known to those skilled in the art. And is selected from copper trifluoromethanesulfonate, copper halide, cuprous iodide, ferric trifluoromethanesulfonate, ferric halide, zinc trifluoromethanesulfonate, zinc halide, etc. According to experimental results, in order to realize multi-coordination of metal and excellent catalytic effect, the trifluoromethanesulfonate is preferably used.

The chiral metal compound and the base used for preparing the chiral technical compound provided by the invention are one or more of various organic bases and inorganic bases which are well known to those skilled in the art, and the preparation of the chiral metal compound is not limited. Among them, organic bases such as triethylamine and DABCO, and inorganic bases such as sodium carbonate and lithium carbonate are most commonly used. In view of the solubility of the base in the solvent, it is generally preferred to use an organic base.

The solvent used for preparing the chiral metal compound can be one or more of ketones, nitriles and halogen-containing compounds. Wherein, the solvents are preferably acetone, acetonitrile, dichloromethane and chloroform.

In a third aspect, the chiral metal complex of the present invention exhibits high-efficiency and excellent catalytic effects for asymmetric Mukaiyama aldol reactions. As can be seen from the following examples, the chiral metal complex generated in situ by using the ligand L2 and the metallic copper has high catalytic effect on Mukaiyama aldol reaction of phenylglyoxal monohydrate and substituted phenylglyoxal monohydrate, and the reaction shows excellent enantioselectivity. The chiral metal ligand compound solves the problems of harsh reaction conditions and multi-step reaction of intermediate conversion, and prepares the beta-hydroxy dicarbonyl compound more efficiently, more environmentally and more conveniently.

Therefore, the invention also provides a simple, convenient and environment-friendly preparation method of the 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound, which comprises the following steps: the chiral metal compound or the chiral metal compound prepared according to the invention is mixed with silicon enol ether and phenylglyoxal monohydrate or substituted phenylglyoxal monohydrate for reaction, so that the 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound can be smoothly obtained, and R of the silicon enol ether₁Is phenyl or furan structure, and substituent R in substituted phenylglyoxal monohydrate₂One or more selected from hydrogen atom, halogen, methyl, methoxy, nitro and trifluoromethyl, and the substituent R₂At the ortho, meta or para position of the phenyl ring.

The concentration of the chiral metal compound participating in the reaction can be 0.5-5 mmol/L; the temperature of the Mukaiyama aldol reaction is-10-25 ℃; the time for the Mukaiyama aldol reaction may be 1-2.5 hours.

In the present invention, the molar ratio of the above-mentioned enolsilyl ether to the chiral metal complex may be (10-20): 1, with a molar ratio of (10-18): 1 is preferred.

The specific embodiment of the preparation of the chiral metal compound of the invention is as follows, taking chiral ligand L2-copper compound as an example: adding a selected solvent into a reaction container, adding copper salt according to a proportion, and stirring for one hour to fully dissolve the copper salt; chiral ligand L2 and base are then added, the reaction vessel is transferred to 0 ℃ and stirred for one hour, the temperature is reduced to slow down the reaction exotherm, the ligand L2 and copper are helped to react uniformly, and the coordination sites of the copper are reserved. The solvent is well known to those skilled in the art, and may be ketones, nitriles, halogen-containing compounds, preferably acetone, acetonitrile, chloroform. The copper salt can be one or more of copper trifluorobenzene sulfonate, copper halide and copper nitrate. The concentration of the copper salt in the solvent may be 0.5-5 mmol/L.

The invention provides an application of the chiral copper-ligand L2 compound as a catalyst of asymmetric Mukaiyama aldol reaction of phenylglyoxal monohydrate or substituted phenylglyoxal monohydrate, and a method for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compounds, wherein the structure of the phenylglyoxal monohydrate or the substituted phenylglyoxal monohydrate is as follows:

specifically, chiral copper complex, enol silyl ether and phenylglyoxal monohydrate shown as a formula (2) are mixed and reacted: the molar ratio of the silyl enol ether to the chiral copper complex can be (10-20): 1, with a molar ratio of (10-18): 1 is preferred; the solvent is well known to those skilled in the art and may preferably be a ketone, nitrile or halogen-containing compound, of which acetone, acetonitrile or chloroform are most commonly used; the concentration of the phenylglyoxal monohydrate with the structure shown in the formula (2) can be 0.1-10mmol/mL, and is optimized to be 0.1-5 mmol/mL; the temperature of the mixing reaction can be-20-30 ℃, the temperature can be optimized to be-20-20 ℃, and the reaction time can be 1-2.5 h.

The reaction equation is shown below (taking phenyl enol silyl ether as a nucleophilic reagent to participate in the reaction as an example):

after the mixed reaction under the optimized condition is separated and purified, the chiral 1, 4-diphenyl-2-hydroxy-1, 4-butanone compound is obtained; the purification method is a separation and purification method well known to those skilled in the art, and comprises extraction liquid separation, liquid chromatography, gas chromatography, recrystallization, distillation and column chromatography separation, and can be optimized to distillation and column chromatography separation; the eluent of the column chromatography separation method is a solvent well known to those skilled in the art, and can be one or more selected from petroleum ether, ethyl acetate, methanol, dichloromethane, benzene and the like, and can be optimized to be a mixed solvent of petroleum ether and ethyl acetate; the optimized volume ratio of petroleum ether to ethyl acetate may be (50-5): 1.

from the above, the invention provides a method for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound by catalyzing asymmetric Mukaiyama aldol reaction of phenylglyoxal monohydrate with Lewis acid of a chiral copper ligand L complex. The method has the advantages of high enantioselectivity, simple and convenient operation, environment-friendly and easily obtained raw materials and catalysts and the like.

All the raw materials of the present invention may be commercially available or may be prepared by themselves according to literature reports, and are not specifically limited.

The equipment used in the following examples:

nuclear magnetic resonance: brooks 400MHzfor¹HNMR and 100MHzfor¹³CNMR nuclear magnetic resonance apparatus

Mass spectrometry: watts Waters^TMQ-TOFPREMIer series

To further illustrate the invention, the efficient catalytic action of chiral metal complexes in asymmetric Mukaiyama aldol reactions of phenylglyoxal monohydrate is detailed below with reference to specific examples.

The structures of the enolsilyl ethers represented by formula 3 and formula 4 used in the following examples are shown below:

example 1

Preparation of proline derived chiral ligand, exemplified by L-proline with a protecting group to prepare chiral ligand L2;

the synthetic route is as follows:

in a three-necked flask filled with nitrogen atmosphere, tetrahydrofuran (20mL) as a solvent was added, magnesium strips (0.36g, 15mmol) and p-methylbromobenzene (1.3g, 7.5mmol) were added, and the reaction was heated by a blower until initiation. The remaining p-methylbromobenzene (1.3g, 7.5mmol) was added dropwise over 20 min. After the dropwise addition, the mixture was further heated to 70 ℃ and refluxed for 2 hours. A solution of benzyl-protected L-proline A (3.3g, 15mmol) in tetrahydrofuran (20mL) was added dropwise to the reaction system, and the reaction was continued at 70 ℃ under reflux for 7 hours. The reaction was monitored for completion by thin layer chromatography and quenched with saturated aqueous ammonium chloride. Extracted with ethyl acetate and back extracted with saturated saline. Drying over anhydrous sodium sulfate and concentrating to obtain benzyl protected amino alcohol compound B.

Compound B (1.11g, 3mmol) prepared above was dissolved in ethanol (30mL), concentrated hydrochloric acid (0.3mL, 12mmol) was added, and hydrogen gas was introduced into the reaction system. And reacting for 8 hours at room temperature under a hydrogen atmosphere. After the reaction was terminated by monitoring by thin layer chromatography, the reaction was terminated, the atmosphere of hydrogen was removed, the reaction mixture was filtered, and the residue was washed with ethanol (30mL), collected, and concentrated under reduced pressure. Subsequently 50mL of acetic acid was added to the system and the pH was adjusted to >9 with the appropriate amount of sodium hydroxide solution. The mixture is extracted by ethyl acetate, and is back extracted by saturated saline solution, dried by adding anhydrous sodium sulfate and concentrated by decompression to obtain the alkamine C for standby.

The aminoalcohol C prepared in the previous step (0.56g, 2mmol) was dissolved in t-butanol (30ml), 2-hydroxy-3-trifluoromethylbenzaldehyde (2mmol) was added, and the reaction was stirred at 30 ℃ for 6 hours. Monitoring the reaction by thin-layer chromatography, concentrating under reduced pressure, separating and purifying the residue by silica gel column chromatography, wherein the eluent is petroleum ether/ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 5:1, thus obtaining chiral ligand L2.

Example 2

Preparation of proline derived chiral ligand, exemplified by L-proline with a protecting group to prepare chiral ligand L3;

the synthetic route is as follows:

in a three-necked flask filled with nitrogen atmosphere, tetrahydrofuran (20mL) as a solvent was added, a magnesium rod (0.36g, 15mmol) and p-methoxybromobenzene (1.4g, 7.5mmol) were added, and the mixture was heated by a blower until the reaction was initiated. The remaining p-methoxybromobenzene (1.4g, 7.5mmol) was added dropwise over 20 min. After the dropwise addition, the mixture was further heated to 70 ℃ and refluxed for 2 hours. A solution of benzyl-protected L-proline A (3.3g, 15mmol) in tetrahydrofuran (20mL) was added dropwise to the reaction system, and the reaction was continued at 70 ℃ under reflux for 7 hours. The reaction was monitored for completion by thin layer chromatography and quenched with saturated aqueous ammonium chloride. Extracted with ethyl acetate and back extracted with saturated saline. Drying over anhydrous sodium sulfate and concentrating to obtain benzyl protected amino alcohol compound B.

Compound B (1.21g, 3mmol) prepared above was dissolved in ethanol (30mL), concentrated hydrochloric acid (0.3mL, 12mmol) was added, and hydrogen gas was passed through the reaction system. And reacting for 8 hours at room temperature under a hydrogen atmosphere. After the reaction was terminated by monitoring by thin layer chromatography, the reaction was terminated, the atmosphere of hydrogen was removed, the reaction mixture was filtered, and the residue was washed with ethanol (30mL), collected, and concentrated under reduced pressure. Subsequently 50mL of acetic acid was added to the system and the pH was adjusted to >9 with the appropriate amount of sodium hydroxide solution. The mixture is extracted by ethyl acetate, and is back extracted by saturated saline solution, dried by adding anhydrous sodium sulfate and concentrated by decompression to obtain the alkamine C for standby.

The aminoalcohol C prepared in the above step (0.63g, 2mmol) was dissolved in t-butanol (30ml), 2-hydroxy-3-trifluoromethylbenzaldehyde (2mmol) was added, and the reaction was stirred at 30 ℃ for 6 hours. And monitoring the reaction by thin-layer chromatography, concentrating under reduced pressure, and separating and purifying the residue by silica gel column chromatography, wherein the eluent is petroleum ether/ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 5:1, so as to obtain chiral ligand L3.

Example 3

Preparation of proline derived chiral ligand, exemplified by L-proline with a protecting group to prepare chiral ligand L4;

the synthetic route is as follows:

in a three-necked flask filled with nitrogen atmosphere, tetrahydrofuran (20mL) as a solvent was added, a magnesium strip (0.36g, 15mmol) and p-trifluoromethylbromobenzene (1.7g, 7.5mmol) were added, and the reaction was heated by a blower until initiation. The remaining p-methylbromobenzene (1.7g, 7.5mmol) was added dropwise over 20 min. After the end of the dropwise addition, heating was continued at 70 ℃ for reflux for 2 h. A solution of benzyl-protected L-proline A (3.3g, 15mmol) in tetrahydrofuran (20mL) was added dropwise to the reaction system, and the reaction was continued at 70 ℃ under reflux for 7 hours. The reaction was monitored for completion by thin layer chromatography and quenched with saturated aqueous ammonium chloride. Extracted with ethyl acetate and back extracted with saturated saline. Drying over anhydrous sodium sulfate and concentrating to obtain benzyl protected amino alcohol compound B.

Compound B (1.44g, 3mmol) prepared above was dissolved in ethanol (30mL), concentrated hydrochloric acid (0.3mL, 12mmol) was added, and hydrogen gas was passed through the reaction system. And reacting for 8 hours at room temperature under a hydrogen atmosphere. After the reaction was terminated by monitoring by thin layer chromatography, the reaction was terminated, the atmosphere of hydrogen was removed, the reaction mixture was filtered, and the residue was washed with ethanol (30mL), collected, and concentrated under reduced pressure. Subsequently 50mL of acetic acid was added to the system and the pH was adjusted to >9 with the appropriate amount of sodium hydroxide solution. The mixture is extracted by ethyl acetate, and is back extracted by saturated saline solution, dried by adding anhydrous sodium sulfate and concentrated by decompression to obtain the alkamine C for standby.

The aminoalcohol C prepared in the previous step (0.78g, 2mmol) was dissolved in t-butanol (30ml), and 2-hydroxy-3-trifluoromethylbenzaldehyde (2mmol) was added thereto, and the reaction was stirred at 70 ℃ for 6 hours. And monitoring the reaction by thin-layer chromatography, concentrating under reduced pressure, and separating and purifying the residue by silica gel column chromatography, wherein the eluent is petroleum ether/ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 5:1, so as to obtain chiral ligand L4.

Example 4

Preparation of chiral copper ligand complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; chiral ligand (4.2mg, 0.1mmol) prepared in example 1 above and triethylamine (2.8 μ L, 0.02mmol) were added and the reaction was transferred to 0 ℃ and stirred for one hour to promote a uniform reaction of ligand L and copper by reducing the temperature to slow the reaction exotherm and preserve the coordination sites of copper.

Example 5

Preparation of chiral metallic iron ligand complex

Adding 1mL of acetone into a 10mL reaction tube, adding ferric trifluoromethanesulfonate (10.0mg, 0.02mmol), and stirring for one hour to fully dissolve ferric salt; chiral ligand (4.2mg, 0.1mmol) prepared in example 1 above and triethylamine (2.8 μ L, 0.02mmol) were added and the reaction was transferred to 0 ℃ and stirred for one hour to promote a uniform reaction of ligand L and copper by reducing the temperature to slow the reaction exotherm and preserve the coordination sites of iron.

Example 6

Preparation of chiral metal zinc ligand complex

Adding 1mL of acetone into a 10mL reaction tube, adding zinc trifluoromethanesulfonate (7.27mg, 0.02mmol), and stirring for one hour to fully dissolve the zinc salt; chiral ligand (4.2mg, 0.1mmol) prepared in example 1 above and triethylamine (2.8 μ L, 0.02mmol) were added and the reaction was transferred to 0 ℃ and stirred for one hour to promote a uniform reaction of ligand L and copper by reducing the temperature to slow the reaction exotherm and preserve the coordination sites of copper.

Example 7

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3aa by catalyzing phenylglyoxal monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; chiral ligand L2(4.2mg, 0.1mmol) prepared in example 1 above and triethylamine (2.8. mu.L, 0.02mmol) were added and the reaction was transferred to 0 ℃ and stirred for one hour to give a chiral copper complex. Phenylglyoxal monohydrate 1a (phenylglyoxal monohydrate) (15.2mg, 0.1mmol) and the silyl enol ether 2a represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ to react for 2.5 hours. After the reaction was monitored by thin layer chromatography, extraction was performed with ethyl acetate, back extraction was performed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography, eluted with a gradient of 20/1 to 5/1 using petroleum ether/ethyl acetate to give the product S-3aa (89% yield, 94% ee) as a white solid.

The target product s-3aa obtained in example 7 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in fig. 1. 1H NMR (400MHz, CDCl 3): δ 7.93-7.86(dd,4H),7.56-7.36(m,6H),5.52(s,1H),4.02(s,1H),3.33(m, 2H).

The target product s-3aa obtained in example 7 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in fig. 2. 13C NMR (100MHz, CDCl 3): δ 200.8, 197.2, 136.6, 134.0, 133.6,133.5, 129.0,128.8, 128,7, 128.3, 100.0, 70.1, 43.6.

Analysis of the target product s-3aa obtained in example 7 by mass spectrometry gave the result HRMS (ESI) M/z, calculated 277.0841 for C16H14O3[ M + Na ] + and 277.0843.

Example 8

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3ba by catalyzing 4-methyl phenylglyoxal monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate 1b (4-methylphenylaldehyde monohydrate) (16.6mg, 0.1mmol) and the silyl enol ether 2a represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ to react for 2.5 hours. After the reaction was monitored by thin layer chromatography, it was extracted with ethyl acetate, back-extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography, eluting with a gradient of petroleum ether/ethyl acetate from 20/1 to 5/1 to afford the product S-3ba as a white solid (88% yield, 95% ee).

The target product s-3ba obtained in example 8 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 3. 1H NMR (400MHz, CDCl 3): δ 7.85, (m, 4H), 7.50(t, 1H), 7.38(t, 2H), 7.22(d, 2H), 5.60(d, 1H),3.30(qd,2H),2.36(d, 3H).

The target product s-3ba obtained in example 8 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 4. 13C NMR (100MHz, CDCl 3): δ 200.3, 197.1, 145.1, 136.6, 133.5, 130.8, 129.6, 128.8, 128.6,128.3, 69.8, 43.8, 21.7.

The analysis of the target product s-3ba obtained in example 8 by means of a mass spectrometer gave the result HRMS (ESI) M/z, calculated 291.0997 for C16H14O3[ M + Na ] + and 291.0999.

Example 9

Preparation of 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3ca by Mukaiyama aldol reaction of 4-methoxy phenylglyoxal monohydrate catalyzed by copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate 1c (4-methoxyphenylglyoxal monohydrate) (18.2mg, 0.1mmol) and the silyl enol ether 2a represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ for reaction for 2.5 hours. After the reaction was monitored by thin layer chromatography, it was extracted with ethyl acetate, back-extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography, eluting with petroleum ether/ethyl acetate in a gradient from 20/1 to 5/1 to give the product S-3ca as a white solid (87% yield, 91% ee).

The target product s-3ca obtained in example 9 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 5. 1H NMR (400MHz, CDCl 3): δ 7.98(ddd,4H),7.57(t,1H),7.46(t,2H),6.97(t,2H),5.67(dd,1H),4.09(dd,1H),3.87(s, 3H).

The target product s-3ca obtained in example 9 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 6. 13C NMR (100MHz, CDCl 3): δ 199.1,197.3,164.3,136.7,133.6,131.2,128.7,128.4,126.1,114.2,69.6,55.6, 44.1.

The target product s-3ca obtained in example 9 was analyzed by a mass spectrometer to obtain the result HRMS (ESI) M/z, calculated value of 307.0946 for C16H14O3[ M + Na ] + and measured value of 307.0949.

Example 10

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3da by catalyzing 4-fluorobenzenedialdehyde monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate 1d (4-fluorophenylglyoxal monohydrate) (17.0mg, 0.1mmol) and the enolsilyl ether 2a represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ for reaction for 2.5 hours. After the completion of the reaction, the reaction was monitored by thin layer chromatography, extracted with ethyl acetate, back-extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography, eluted with a gradient of 20/1 to 5/1 using petroleum ether/ethyl acetate to give the product S-3da as a white solid (83% yield, 87% ee).

The target product s-3da obtained in example 10 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 7. 1H NMR (400MHz, CDCl 3): δ 8.06(m,2H),7.95(m,2H),7.59(m,1H),7.47(t,2H),7.17(m,2H),5.61(td,1H),4.03(d,1H),3.41(qd,2H)

The target product s-3da obtained in example 10 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 8. 13C NMR (100MHz, CDCl 3): delta 199.1,197.5,167.4,164.9,136.5,133.7,131.7,131.6,131.5,128.7,128.3,116.3,116.1,70.2,43.3

The target product s-3da obtained in example 10 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance fluorine spectrum, as shown in FIG. 9. The NMR spectrum showed fluorine atoms in the product.

The analysis of the objective product s-3da obtained in example 10 by means of a mass spectrometer gave the result HRMS (ESI) M/z, calculated value of 295.0746 for C16H14O3[ M + Na ] + and a measured value of 295.0749.

Example 11

Preparation of 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3ea by Mukaiyama aldol reaction of 4-chlorobenzenedialdehyde monohydrate catalyzed by copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate 1e (4-chlorobenzenedialdehyde monohydrate) (18.6mg, 0.1mmol) and the silyl enol ether 2a represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ to react for 2.5 hours. After the reaction was monitored by thin layer chromatography, extraction was performed with ethyl acetate, back extraction was performed with saturated brine, drying was performed with anhydrous sodium sulfate, concentration was performed under reduced pressure, and the residue was separated by column chromatography, and eluted with petroleum ether/ethyl acetate at a gradient of 20/1 to 5/1 to give S-3ea as a white solid product (75% yield, 95% ee).

The target product s-3ea obtained in example 11 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in fig. 10. 1H NMR (400MHz, CDCl 3): delta 7.97-7,. 94(dd, 4H), 7.61-7.57(t,1H),7.52-7.44(t,4H),5.58(dd,1H),4.01(d,1H),4.11-3.24(qd,2H)

The target product s-3ea obtained in example 11 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in fig. 11. 13C NMR (100MHz, CDCl 3): delta 199.5,197.5,140.4,136.5,133.8,132.1,130.3,129.3,128.8,128.3,70.3,43.2

The target product s-3ea obtained in example 11 was analyzed by a mass spectrometer to obtain the result HRMS (ESI) M/z, the calculated value for C16H14O3[ M + Na ] + was 311.0451, and the measured value was 311.0451.

Example 12

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3fa by catalyzing 4-bromophenylglyoxal monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate 1f (4-bromophenylglyoxal monohydrate) (23.1mg, 0.1mmol) and the silyl enol ether 2a represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ for reaction for 2.5 hours. After the reaction was monitored by thin layer chromatography, it was extracted with ethyl acetate, back-extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography, eluting with petroleum ether/ethyl acetate in a gradient from 20/1 to 5/1 to give the product S-3fa as a white solid (80% yield, 98% ee).

The target product s-3fa obtained in example 12 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in fig. 12. 1H NMR (400MHz, CDCl 3): δ 7.87(d,2H),7.81(d,2H),7.57(d,2H),7.52(t,1H),7.40(t,2H),5.50(dd,1H),3.93(d,1H),3.35(qd,2H)

The target product s-3fa obtained in example 12 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in fig. 13. 13C NMR (100MHz, CDCl 3): delta 199.6,197.5,133.8,132.3,130.3,128.8,128.3,70.4,43.1

The analysis of the target product s-3fa obtained in example 12 by a mass spectrometer gave the result HRMS (ESI) M/z, calculated value of 354.9946 for C16H14O3[ M + Na ] + and found value of 354.9941.

Example 13

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3ga by catalyzing 4-trifluoromethyl phenylglyoxal monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. 1g of phenylglyoxal monohydrate (22.0mg, 0.1mmol) and the above-mentioned silyl enol ether 2a represented by the formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ to react for 2.5 hours. After the reaction was monitored by thin layer chromatography, it was extracted with ethyl acetate, back-extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography, eluting with a gradient of 20/1 to 5/1 using petroleum ether/ethyl acetate to give the product S-3ga as a white solid (70% yield, 89% ee).

The target product s-3ga obtained in example 11 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 13. 1H NMR (400MHz, CDCl 3): δ 8.0(t,2H),7.87(m,2H),7.70(d.2H),7.53(t,1H),7.41(m,2H),5.50(d,1H),3.96(t,1H),3.41(m,2H)

The target product s-3ga obtained in example 13 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 15. 13C NMR (100MHz, CD3 OD): delta 199.1,198.0,138.5,136.7,134.0,133.2,129.2,128.4,127.9,125.3,125.2,69.4,42.0

The target product s-3ga obtained in example 13 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance fluorine spectrum, as shown in FIG. 16. The nuclear magnetic resonance fluorine spectrum shows that the product contains fluorine atoms.

The target product s-3ga obtained in example 13 was analyzed by a mass spectrometer to obtain the result HRMS (ESI) M/z, calculated value for C16H14O3[ M + Na ] + was 345.0714, and measured value was 345.0710.

Example 14

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3ha by catalyzing 3-methyl phenylglyoxal monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate (16.6mg, 0.1mmol) and the above-mentioned silyl enol ether 2a represented by formula 3 (42. mu.L, 0.2mmol) were added to the system for 1 hour, and the reaction system was transferred to 5 ℃ to react for 2.5 hours. After the reaction was monitored by thin layer chromatography, extraction was performed with ethyl acetate, back extraction was performed with saturated brine, drying was performed with anhydrous sodium sulfate, concentration was performed under reduced pressure, and the residue was separated by column chromatography, and gradient elution was performed with petroleum ether/ethyl acetate from 20/1 to 5/1 to obtain S-3ha (90% yield, 93% ee) as a white solid product.

The target product s-3ha obtained in example 14 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in fig. 17. 1H NMR (400MHz, CDCl 3): δ 7.91-7.88(m,2H),7.62-7.54(m,2H),7.46-7.39(m,3H),7.31-7.29(m,2H),5.47(dd,1H),3.46-3.30(ddd,2H),2.55(d,3H)

The target product s-3ha obtained in example 14 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in fig. 18. 13C NMR (100MHz, CD3 OD): delta 201.1,197.1,139.0,136.7,134.8,133.6,133.5,129.2,128.8,128.7,128.4,125.9,70.0,43.7,21.4

The target product s-3ha obtained in example 14 was analyzed by a mass spectrometer to obtain the result HRMS (ESI) M/z, calculated 291.0997 for C16H14O3[ M + Na ] + and 291.1003.

Example 15

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3ia by catalyzing 3-methoxy phenylglyoxal monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate 1i (3-methoxyphenylglyoxal monohydrate) (18.2mg, 0.1mmol) and the silyl enol ether 2a represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ for reaction for 2.5 hours. After the reaction was monitored by thin layer chromatography, it was extracted with ethyl acetate, back-extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography, eluting with petroleum ether/ethyl acetate in a gradient from 20/1 to 5/1 to give the product S-3ia as a white solid (87% yield, 93% ee).

The target product s-3ia obtained in example 15 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 19. 1H NMR (400MHz, CDCl 3): δ 7.88-7.85(dd,2H),7.49-7.40(m,3H),7.39-7.30(m,3H),7.09-7.06(m,1H),5.60-5.56(dd,1H),3.79(s,3H),3.39-3.28(m,2H)

The target product s-3ia obtained in example 15 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 20. 13C NMR (100MHz, CD3 OD): delta 200.7,197.1,160.2,136.6,134.9,133.6,130.0,128.7,128.3,121..2,120.5,113.0,70.1,55.5,43.7

The target product s-3ia obtained in example 15 was analyzed by a mass spectrometer to obtain the result HRMS (ESI) M/z, calculated value for C16H14O3[ M + Na ] + being 307.0941 and found value being 307.0943.

Example 16

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3ja by catalyzing 3-chlorobenzenedialdehyde monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate 1j (3-chlorobenzenedialdehyde monohydrate) (18.7mg, 0.1mmol) and the silyl enol ether 2a represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ to react for 2.5 hours. After the reaction is monitored by thin layer chromatography, the product is extracted by ethyl acetate, back extracted by saturated saline, dried by anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is separated by column chromatography and eluted by petroleum ether/ethyl acetate in a gradient from 20/1 to 5/1 to obtain a white solid product S-3ja (73% yield and 89% ee).

The target product s-3ja obtained in example 16 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 21. 1H NMR (400MHz, CDCl 3): δ 7.99(s,1H),7.96-7.93(d,2H),7.89-7.86(d,2H),7.61-7.56(t,2H),7.49-7.42(dd,3H),5.56(s,1H),3.99(s,1H),3.60-3.27(m,2H)

The target product s-3ja obtained in example 16 was analyzed by nmr to obtain an nmr carbon spectrum, as shown in fig. 22. 13C NMR (100MHz, CD3 OD): delta 199.6,197.5,136.4,135.5,135.3,133.8,130.2,128.9,128.8,128,4,126.9,70.5,43.0,29.7

The analysis of the target product s-3ja obtained in example 16 by means of a mass spectrometer gave the result HRMS (ESI) M/z, calculated 311.0451 for C16H14O3[ M + Na ] + and 311.0453.

Example 17

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3ka by catalyzing 2-methyl phenylglyoxal monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate 1k (2-methylglyoxal monohydrate) (16.6mg, 0.1mmol) and the silyl enol ether 2a represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ for reaction for 2.5 hours. After the reaction was monitored by thin layer chromatography, it was extracted with ethyl acetate, back-extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography, eluting with petroleum ether/ethyl acetate in a gradient from 20/1 to 5/1 to give the product S-3ka as a white solid (89% yield, 95% ee).

The target product s-3ka obtained in example 17 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 23. 1H NMR (400MHz, CDCl 3): δ 7.90(d,2H),7.62-7.54(m,2H),7.46-7.39(m,2H),7.32-7.26(m,3H),5.46(m,1H),4.05(d,1H),3.46-3.30(ddd,2H),2.58(s,3H)

The target product s-3ka obtained in example 17 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 24. 13C NMR (100MHz, CD3 OD): delta 201.1,197.1,139.0,136.7,134.8,133.6,133.5,129.2,128.8,128.7,128.4,125.9,70.0,43.7,21.4

The target product s-3ka obtained in example 17 was analyzed by a mass spectrometer to obtain the result HRMS (ESI) M/z, the calculated value for C16H14O3[ M + Na ] + was 291.0997, and the measured value was 291.0999.

Example 18

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3la by catalyzing 2-nitrophenylglyoxal monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. 1L of phenylglyoxal monohydrate (19.7mg, 0.1mmol) and the above-mentioned silyl enol ether 2a represented by formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ to react for 2.5 hours. After the reaction was monitored by thin layer chromatography, it was extracted with ethyl acetate, back-extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography, eluting with petroleum ether/ethyl acetate in a gradient from 20/1 to 5/1 to give S-3la (79% yield, 91% ee) as a white solid.

The target product s-3la obtained in example 18 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in fig. 25. 1H NMR (400MHz, CDCl 3): δ 8.08(d,1H),7.90(m,2H),7.72(m,1H),7.60-7.50(m,2H),7.48-7.40(m,3H),4.96(d,1H),3.66(d,2H),3.42(d,1H)

The target product s-3la obtained in example 18 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in fig. 26. 13C NMR (100MHz, CD3 OD): delta 205.4,199.7,134.4,134.1,130.9,129.1,128.8,128.3,123.6,73.4,42.8,

the target product s-3la obtained in example 18 was analyzed by a mass spectrometer to obtain the result HRMS (ESI) M/z, the calculated value for C16H14O3[ M + Na ] + was 322.0691, and the measured value was 322.0693.

Example 19

Preparation of 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3ma by Mukaiyama aldol reaction of 2-chlorobenzenedialdehyde monohydrate catalyzed by copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. 2-Chlorobenzenedialdehyde monohydrate 1m (18.7mg, 0.1mmol) and enolsilyl ether 2a represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ for reaction for 2.5 hours. After the reaction was monitored by thin layer chromatography, extraction was performed with ethyl acetate, back extraction was performed with saturated brine, drying was performed with anhydrous sodium sulfate, concentration was performed under reduced pressure, and the residue was separated by column chromatography, and gradient elution was performed with petroleum ether/ethyl acetate from 20/1 to 5/1 to obtain a white solid product S-3ma (72% yield, 94% ee).

The target product s-3ma obtained in example 19 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 27. 1H NMR (400MHz, CDCl 3): δ 7.99(s,1H),7.94(d,2H),7.88(d,1H),7.61-7.56(t,2H),7.49-7.44(t,3H),5.56(s,1H),3.99(s,1H),3.44(s,2H)

Analysis of the objective product s-3ma obtained in example 19 by nuclear magnetic resonance gave a nuclear magnetic resonance carbon spectrum, as shown in FIG. 28 by 13C NMR (100MHz, CD3 OD): delta 199.6,197.5,136.4,135.5,135.3,133.8,130.2,128.9,128.8,128,4,126.9,70.5,43.0

Analysis of the target product s-3ma obtained in example 19 by means of a mass spectrometer gave the result HRMS (ESI) M/z, calculated 311.0451 for C16H14O3[ M + Na ] + and 311.0457.

Example 20

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3na by catalyzing 2-fluorobenzenedialdehyde monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate 1n (2-fluorophenylglyoxal monohydrate) (17.0mg, 0.1mmol) and the enolsilyl ether represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ for reaction for 2.5 hours. After the reaction was monitored by thin layer chromatography, it was extracted with ethyl acetate, back-extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography, eluting with petroleum ether/ethyl acetate in a gradient from 20/1 to 5/1 to give S-3na as a white solid product (80% yield, 94% ee).

The target product s-3na obtained in example 20 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 29. 1H NMR (400MHz, CDCl 3): δ 7.91-7.83(m,3H),7.51-7.45(m,2H),7.39-7.34(t,2H),7.24-7.18(dd,1H),7.10-7.04(dd,1H),5.32-5.28(dt,1H),3.99(s,1H),3.57-3.51(ddd,1H),3.31-3.25(dd,1H)

The target product s-3na obtained in example 20 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 30. 13C NMR (100MHz, CD3 OD): delta 199.6,199.5,197.1,162.3,159.8,136.5,135.3,135.2,133.6,131.5,131.4,128.7,128.3,125.1,125.0,116.7,116.5,73.4,73.3,42.3,29.7

The target product s-3na obtained in example 20 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 31. The nuclear magnetic resonance fluorine spectrum shows that the product contains fluorine atoms.

The target product s-3Na obtained in example 20 was analyzed by a mass spectrometer to obtain the result HRMS (ESI) M/z, the calculated value for C16H14O3[ M + Na ] + was 295.0746, and the measured value was 295.0743.

Example 21

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3oa by catalyzing 2-methoxy phenylglyoxal monohydrate with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate 1o (2-methoxyphenylglyoxal monohydrate) (18.2mg, 0.1mmol) and the silyl enol ether 2a represented by the above formula 3 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ for reaction for 2.5 hours. After the reaction was monitored by thin layer chromatography, extraction was performed with ethyl acetate, back extraction was performed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography, eluted with a gradient of 20/1 to 5/1 using petroleum ether/ethyl acetate to give the product S-3oa as a white solid (83% yield, 99% ee).

The target product s-3oa obtained in example 21 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in fig. 32. 1H NMR (400MHz, CDCl 3): δ 7.87-7.83(m,3H),7.50-7.43(m,2H),7.39-7.34(t,2H),7.03-6.98(t,1H),6.91-6.88(d,1H),5.54(d,1H),4.04(s,1H),3.81(s,3H),3.41-3.32(dd,1H),3.19-3.12(dd,1H)

The target product s-3oa obtained in example 21 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in fig. 33. 13C NMR (100MHz, CD3 OD): delta 202.2,197.1,158.5,136.9,134.8,133.3,131.7,128.6,128.3,124.0,121.3,111.7,73.5,55.7,42.9

The target product s-3oa obtained in example 21 was analyzed by mass spectrometer to obtain the result hrms (esi) M/z, the calculated value for C16H14O3[ M + Na ] + was 307.0946, and the measured value was 307.0953.

Example 22

Mukaiyama aldol reaction for preparing 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound S-3ab by catalyzing furan-derived enol silyl ether with copper-chiral ligand L2 complex

Adding 1mL of acetone into a 10mL reaction tube, adding copper trifluoromethanesulfonate (7.22mg, 0.02mmol), and stirring for one hour to fully dissolve copper salt; the chiral ligand (4.2mg, 0.1mmol) prepared in the above example 1 and triethylamine (2.8. mu.L, 0.02mmol) were added, and the reaction was transferred to 0 ℃ and stirred for one hour to obtain a chiral copper complex. Phenylglyoxal monohydrate 1a (2- (furan-2-yl) -2-oxoacetaldehyde) (15.2mg, 0.1mmol) and the furan-derived silyl enol ether 2b represented by the above formula 4 (42. mu.L, 0.2mmol) were added to the system, and the reaction system was transferred to 5 ℃ for reaction for 2.5 hours. After the reaction was monitored by thin layer chromatography, extraction was performed with ethyl acetate, back extraction was performed with saturated brine, drying was performed with anhydrous sodium sulfate, concentration was performed under reduced pressure, and the residue was separated by column chromatography, and gradient elution was performed with petroleum ether/ethyl acetate from 20/1 to 5/1 to obtain S-3ab (89% yield, 94% ee) as a white solid product.

The target product s-3ab obtained in example 22 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 34. 1H NMR (400MHz, CDCl 3): δ 7.94-7.91(m,2H),7.57-7.51(m,2H),7.46-7.41(dd,2H),7.17-7.15(dd,1H),6.48-6.46(dd,1H),5.57(t,1H),3.93(s,1H),3.21-3.11(m,2H)

The target product s-3ab obtained in example 22 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 35. 13C NMR (100MHz, CD3 OD): delta 200.5,185.8,152.5,147.0,134.1,133.4,129.0,128.8,118.2,112.6,69.9,43.7

The analysis of the target product s-3ab obtained in example 22 by means of a mass spectrometer gave the result HRMS (ESI) M/z, calculated value of 267.0633 for C16H14O3[ M + Na ] + and found value of 267.0636.

It should be noted that, according to the above embodiments of the present invention, those skilled in the art can fully implement the full scope of the present invention as defined by the independent claims and the dependent claims, and implement the processes and methods as the above embodiments; and the invention has not been described in detail so as not to obscure the present invention. The above description is only a part of the embodiments of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.

Claims

1. A preparation method of chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compounds is characterized by comprising the following steps: in the presence of a chiral metal compound, mixing and reacting enol silicon ether and phenylglyoxal monohydrate or substituted phenylglyoxal monohydrate in a solvent to obtain a chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound; wherein the mol ratio of the enol silyl ether to the chiral metal compound is (10-20): 1, the reaction is shown in the following formula 1:

2. The method of claim 1, wherein the molar ratio of the silyl enol ether to the chiral metal complex is (10-18): 1.

3. the method of claim 1, wherein the chiral metal complex has a general structure represented by A or A',

wherein X^-Selected from trifluoromethanesulfonic acidOne or more of acid radical, halogen ion, acetate radical and nitrate radical; m is selected from one or more of metallic copper, iron and zinc; r_mDenotes a number m of radicals R, R'_nThe expression n groups R ', R, R' are respectively and independently selected from one or more of hydrogen atoms, alkyl groups of C1-C5, alkoxy groups of C1-C5 and perfluoroalkyl groups of C1-C5, m is an integer of 1-5, n is an integer of 1-5, R, R 'is respectively and independently at ortho position, meta position or para position of a benzene ring, and the substitution positions of R and R' on the benzene ring in the same ligand are the same or different.

4. The method of claim 1, wherein the concentration of the phenylglyoxal monohydrate or substituted phenylglyoxal monohydrate is from 0.1 to 10 mmol/mL; preferably, the concentration of the phenylglyoxal monohydrate or the substituted phenylglyoxal monohydrate is 0.1-5 mmol/mL.

5. The method of claim 1, wherein the temperature of the mixing reaction is-20-30 ℃; preferably, the temperature of the mixing reaction is-20-20 ℃; more preferably, the temperature of the mixing reaction is-10-20 ℃.

6. The method of claim 1, wherein the mixing reaction time is 1-2.5 hours.

7. The method as claimed in claim 1, wherein the concentration of the chiral metal complex participating in the reaction is 0.5-5 mmol/mL.

8. The method of claim 1, wherein the solvent is a ketone, nitrile, or a halogen-containing compound; preferably, the solvent is acetone, acetonitrile or chloroform.